Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta

Vashe Chandrakanthan; Prunella Rorimpandey; Fabio Zanini; Diego Chacon; Jake Olivier; Swapna Joshi; Young Chan Kang; Kathy Knezevic; Yizhou Huang; Qiao Qiao; Rema A Oliver; Ashwin Unnikrishnan; Daniel R Carter; Brendan Lee; Chris Brownlee; Carl Power; Robert Brink; Simon Mendez-Ferrer; Grigori Enikolopov; William Walsh; Berthold Göttgens; Samir Taoudi; Dominik Beck; John E Pimanda

doi:10.1038/s41556-022-00955-3

Mesoderm-derived PDGFRA⁺ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta

Nat Cell Biol. 2022 Aug;24(8):1211-1225. doi: 10.1038/s41556-022-00955-3. Epub 2022 Jul 28.

Authors

Vashe Chandrakanthan^#^{1

2}, Prunella Rorimpandey^{3

4}, Fabio Zanini^{3

5

6

7}, Diego Chacon⁸, Jake Olivier⁹, Swapna Joshi^{3

4}, Young Chan Kang^{3

4}, Kathy Knezevic^{3

4}, Yizhou Huang^{5

9

10}, Qiao Qiao³, Rema A Oliver¹¹, Ashwin Unnikrishnan^{3

5}, Daniel R Carter^{5

9

10}, Brendan Lee¹², Chris Brownlee¹², Carl Power¹², Robert Brink^{13

14}, Simon Mendez-Ferrer¹⁵, Grigori Enikolopov¹⁶, William Walsh¹¹, Berthold Göttgens¹⁵, Samir Taoudi^{17

18}, Dominik Beck⁸, John E Pimanda^#^{19

20

21}

Affiliations

¹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. v.chandrakanthan@unsw.edu.au.
² Department of Pathology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. v.chandrakanthan@unsw.edu.au.
³ Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
⁴ Department of Pathology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁵ School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
⁶ Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia.
⁷ UNSW Futures Institute for Cellular Genomics, Sydney, Australia.
⁸ Centre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia.
⁹ School of Mathematics and Statistics, UNSW Sydney, Sydney, NSW, Australia.
¹⁰ Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
¹¹ Surgical & Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW, Australia.
¹² Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
¹³ Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁴ UNSW Sydney, Sydney, NSW, Australia.
¹⁵ Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁶ Center for Developmental Genetics and Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
¹⁷ Epigenetics and development division, Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
¹⁸ Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
¹⁹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia. jpimanda@unsw.edu.au.
²⁰ Department of Pathology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. jpimanda@unsw.edu.au.
²¹ Department of Haematology, The Prince of Wales Hospital, Sydney, NSW, Australia. jpimanda@unsw.edu.au.

^# Contributed equally.

Abstract

Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition. We investigated whether mesenchymal stem cells, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta-gonad-mesonephros and contribute to the development of the dorsal aorta and endothelial-to-haematopoietic transition. Here we show that mesoderm-derived PDGFRA⁺ stromal cells (Mesp1^der PSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5-E11.5 aorta-gonad-mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1^der PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1^der PSCs but not Wnt1^der PSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT and NOTCH signalling interrupted this reprogramming event. Together, aorta-gonad-mesonephros Mesp1^der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta
Hemangioblasts*
Hematopoiesis / genetics
Hematopoietic Stem Cells
Mesoderm
Mesonephros*
Mice

Abstract

Publication types

MeSH terms

Grants and funding